Ligand-targeted therapeutics are a rapidly growing class of anticancer agents. This class of therapeutics is typically bifunctional molecules that use a targeting moiety to selectively deliver potent, typically nonspecific, cytotoxic agents to cancer cells while sparing normal cells. The low-molecular-weight of ligant-targeted therapeutics allows for better tumor penetration, especially in the case of solid tumors where the size of antibodies is a limiting factor for effective treatment. Unfortunately, the poor pharmacokinetic profiles of many of these conjugates present a challenge, which limits their tremendous therapeutic potential. Dose-limiting toxicity is also observed due to the need for high doses and frequent administration. This dissertation describes our work to develop a fundamentally new approach for targeting cancer. Our approach could potentially reduce the toxicity and enhance the pharmacokinetic properties of targeted anticancer agents, which would decrease dosing frequency and improve the lives of cancer patients.

<p>  </p> <p>As the pharmaceutical industry moves towards molecular obesity with the use of high throughput screening for identification of promising candidates, the low aqueous solubilities of new chemical entities pose significant challenges to achieving adequate oral absorption and bioavailability. Enabling formulations are often needed to address this issue. Amorphous solid dispersion (ASD), where an amorphous drug and a polymer are molecularly mixed, has gained popularity as a dissolution/solubility enhancing strategy over the years. Upon ASD dissolution, the release rate of drug is much higher than that of the neat amorphous form of the drug. More importantly, the apparent concentration of drug in the solution can exceed its amorphous solubility through the formation of a drug-rich colloidal phase in the solution, also called nanodroplets. The presence of nanodroplets has been shown to be beneficial for oral absorption and bioavailability and their formation during release is therefore desirable. However, such release profiles are only achieved at relatively low drug loadings (DLs) and release tends to drop with increasing DL. For ASDs based on polyvinylpyrrolidone/vinyl acetate (PVPVA), drug release drops drastically once the DL exceeds a certain value, called limit of congruency (LoC). The low DL at which the ASD demonstrates good release also presents additional challenges since it can create a pill burden for patients due to the large amount of polymer needed in the formulation. Therefore, to achieve optimal drug product performance, it is crucial to understand the mechanisms of drug release. Therefore, this thesis focuses on understanding the factors affecting, and the mechanisms of ASD drug release, as well as enhancing drug release through addition of surfactants. </p> <p>The glass transition temperature of a drug and its interaction with the polymer were identified as important factors affecting the drug release and LoC. Another phase transition occurring during ASD hydration/dissolution, amorphous-amorphous phase separation (AAPS), was shown to affect drug release from ASD significantly. During dissolution, water-induced AAPS occurs, and the initially miscible ASD separates into two phases, an insoluble drug-rich phase and a soluble water/polymer-rich phase. The formation of a continuous drug-rich phase at the ASD-solution interface was shown to be detrimental to drug release as it could act as barrier that blocked any further drug release. When the drug-rich phase formed adopted a discrete morphology or when phase separation occurred in the solution outside of the dissolving ASD matrix, good release could be achieved. Surfactants could interrupt the formation of the continuous drug-rich both kinetically and thermodynamically, improving drug release as a result. Other mechanisms of release enhancement by surfactants included increased polymer release rate, increased water ingress and plasticization. The findings in this thesis will provide insight into ASD release mechanisms, and facilitate rational excipient selection when designing ASD formulations.  </p>

<p>This thesis describes the initial steps towards the use of dipeptidyl acyloxymethyl ketones as a platform to develop molecular imaging (MI) probes for cancer. Initially the synthesis of an AOMK was performed following a literature procedure which resulted in an epimerized product. This issue was addressed by optimizing an alternative method yielding all intermediates in yields similar or better to those reported in the literature (final product yield of 67%). An AOMK derivative that can be used to evaluate target expression levels was synthesized by linking a fluorescent dye to the ε-amine group of lysine in accordance to a literature procedure describing the synthesis of an optical imaging probe in 24% yield. A second generation derivative AOMK was prepared by linking 4-fluoro-benzoic acid to the same amino group yielding a model of a PET MI probe.</p> <p>An endpoint colorimetric assay was developed and optimized to test cathepsin B inhibitors. Due to the fact that the AOMKs exhibit time-dependent inhibition these assay conditions did not prove to be adequate for the assessment of the cathepsin B binding. Steps toward developing a continuous assay that would be better suited for these compounds were achieved. Factors such as the relationship between the formation of the assay product vs enzyme concentration and determination of the Michelis-Menten constant (K_m = 390 ± 30 nM) were established. These parameters can be used to determine the optimal enzyme and substrate concentration that should be used to test the AOMK based probes.</p> / Master of Science (MSc)

<p><strong>Background </strong></p> <p>The EQ-5D is one of the most widely used instruments to measure health status. It consists of a descriptive profile with a corresponding scoring algorithm. Multiple scoring algorithms have since been developed from EQ-5D preference elicitation studies.</p> <p><strong>Objectives </strong></p> <p>To identify key methodological issues in the construction of EQ-5D preference elicitation studies and to assess the validity of using a standard methodology in the construction of EQ-5D scoring algorithms.</p> <p><strong>Search methods </strong></p> <p>We searched the MEDLINE, EMBASE, Cochrane Library, NHS Economic Evaluation Database, and Health Economic Evaluation Database, (1990 to 2012). The EuroQol Group website was also searched.</p> <p><strong>Selection criteria </strong></p> <p>EQ-5D preference elicitation studies that reported the directly estimated health state scores and estimated scoring algorithm.</p> <p><strong>Data collection and analysis </strong></p> <p>Two reviewers independently assessed articles for inclusion. The observed and estimated EQ-5D preference scores were compared across studies. A standard scoring algorithm with fixed variables was estimated. The model performance of the standard algorithm and the study reported algorithm were assessed and compared.</p> <p><strong>Results </strong></p> <p>A total of 38 preference elicitation studies were included in this review. Key differences identified include: method of valuation, selection of health states, transformation of health state values, and method of estimation of the scoring algorithm. The observed health state values were found to be significantly different. The predicted health state values showed high levels of rank correlation. In general, a standard scoring algorithm was found to be no different in model performance than study specific scoring algorithms, with only three studies reporting a significant better model performance using the study specified scoring algorithm.</p> <p><strong>Conclusion</strong></p> <p>Methodological differences were identified across EQ-5D valuation studies. A standard scoring algorithm may yield similar model performance to study specific scoring algorithms, however further research is needed to identify when the use of a standard algorithm is appropriate.</p> / Master of Science (MSc)

Natural products are of great significance to the pharmaceutical industry in the development of new drugs. Diquinane or bicyclo[3.3.0]octane is a conspicuous structural unit existing in the carbo-frameworks of a wide range of natural products such as alkaloids and terpenoids. These diquinane-containing molecules not only exhibit intriguing architectures, but also showcase a broad spectrum of significant bioactivities, which draw widespread attention from the global synthetic community. A more specific group of compounds containing a diquinane moiety with one extra 5-membered ring are called the angular triquinanes.In this work, we have developed a general synthetic scheme to the angular triquinanes. We envisioned relatively quick access to the angular triquinane ring system, with each ring bearing synthetically useful functionalization, by direct palladium catalyzed [3+2] cycloaddition of a trimethylenemethane (TMM) unit with functionalized bicyclo[3.3.0]octeneones. This was performed with two different realized bicyclo[3.3.0]octenone substrates. The bicyclo[3.3.0]octeneones can be obtained by [3+2] addition of a TMM-based diradical with an olefin. This synthetic approach allows for the access of trisubstituted angular triquinanes with substitution on each of the three rings in the system, conveniently designed for further derivatization into more complex structures. One of the resulting angular triquinanes from our designed synthesis, containing all-cis fused stereochemistry, was further elaborated to display its utility as an easily manipulated angular triquinane containing a ketone equivalent on each of the three rings in the system. Some diquinane intermediates and final triquinane products were subjected to a biological assay to examine potential cytotoxicity against MDA-MB-468 cancer cells. Additionally, we have designed molecules containing both cyclopentane and polyquinane (diquinane and triquinane) ring systems as DNA polymerase α inhibitors based initially on the structure of the known DNA polymerase α inhibitor, aphidicolin. Optimal design was determined and predicted by docking of the designed ligands to the binding pocket in the active site in the crystal structure of DNA polymerase α (4Q5V) through several iterations with the use of Autodock Vina software. Some of the top designed inhibitors with respect to their binding affinity were synthesized in the laboratory and subjected to a human DNA polymerase α assay.

The opioid crisis remains a severe public health challenge, exacerbated by the high incidence of overdose deaths associated with powerful synthetic opioids like fentanyl. Naloxone, an opioid antagonist, is a critical component in emergency responses to these overdoses due to its ability to rapidly reverse opioid effects. However, naloxone’s short duration of action limits its efficacy, particularly in environments with delayed medical follow-up. This dissertation presents a novel naloxone delivery system utilizing advanced prodrug technology to extend its therapeutic effects. The proposed system, based on a compound, AG10-Linker that enhances naloxone’s pharmacokinetic profile by modulating the solubility and absorption of a naloxone prodrug, thereby facilitating controlled and extended release of naloxone. This research investigates the synthesis, physicochemical properties, and in vivo efficacy of a naloxone prodrug formed by conjugating naloxone with AG10-Linker, demonstrating its potential to provide sustained protection against opioid toxicity. The findings suggest that this innovative approach could significantly impact clinical practice and the broader field of addiction medicine by improving outcomes in managing opioid overdoses.

The main purpose of the research described in this dissertation was to evaluate various aspects of cocaine in pharmacokinetics and pharmacodynamics including: physiologically based-pharmacokinetics modeling; the influence of ethanol on cocaine disposition. Further, cocaine and cocaethylene (CE) were compared using pharmacokinetic-pharmacodynamic (PK-PD) models. Lastly, PK-PD models after cocaine and a combination of cocaine and ethanol dose were developed. Cocaine was administered by iv with or without ethanol in rats. CE was formed only in the group of rats given cocaine in the presence of ethanol. The extent of benzoylecgonine formation from cocaine significantly suppressed in the presence of ethanol. There were no statistical differences in cocaine disposition kinetics following iv cocaine dose in the presence or absence of ethanol. The PB-PK model was developed to describe cocaine disposition in the rat, dog, monkey and ultimately for scaling to humans using information developed in animals. The model gave a good prediction of tissue concentration-time profiles in animals. The prediction of the plasma concentration-time data in humans was poor when using the same tissue-to-blood-partition coefficients (R) obtained in rats. However, an excellent prediction was obtained after R was adjusted for differences in the apparent volume of distribution at steady state (rat vs. humans). The PK-PD model for cocaine or CE was developed by analyzing literature data. CE appears to be less potent in producing euphorigenic effects and equipotent to cocaine in producing physiological effects (e.g., cardiovascular function). The sigmoid Emax model was selected to describe the relationship between the physiological and euphorigenic effects produced by cocaine, ethanol and CE and their respective concentrations in the effect compartment. This model gave a good prediction for those effects. It appears that increased heart rate and "cocaine high" after a combination dose of cocaine and ethanol compared to cocaine alone was due to both the increase in cocaine concentration and the CE formed following ethanol exposure. Similarly, increased effect of "any high" or "good effect" after a combined dose appears to be due to cocaine (in the presence of ethanol), ethanol and CE formed in the presence of cocaine and ethanol.

This dissertation discusses some aspects of the solubilization of drugs from the perspective of the formulator. Chapter I emphasizes the importance of this research as well as the study of the practical aspects of aqueous solubilization of drugs. The most important solubilization techniques such as pH control, cosolvency, micellization, and complexation are introduced in Chapter II. Chapter III evaluates specifically the cosolvency technique by means of a discussion of the effect of pharmaceutically acceptable cosolvents upon the solubilization of several drugs. Chapter IV discusses the micellization technique in detail. In this chapter, the effect of Tween 80 on the solubilization of several drugs is evaluated. Finally, in Chapter V, the consequences of the dilution of a pH solubilized formulation are evaluated by means of two in vitro formulation dilution methods.

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